In the United States alone, approximately 450,000 people yearly suffer a cardiac arrest outside the hospital. Less than 10% of these patients are discharged from the hospital alive, and of these, approximately 60% suffer some form of permanent neurologic injury. The poor outcomes result in part from the low level of myocardial and cerebral blood flow and oxygen delivery generated during standard external CPR following a prolonged cardiopulmonary arrest. While epinephrine, which is an alpha-1,2; beta-1,2 adrenergic agonist, is used during CPR to enhance perfusion, new drugs are needed to optimize hemodynamics and minimize toxicity (i.e., increases in oxygen consumption and ventricular dysrhythmias) in this setting.
Adrenergic agonists are used in CPR to augment cerebral (CePP) and coronary perfusion pressure (CPP). The present inventors have earlier demonstrated an increase in aortic diastolic pressure, the main component of CPP, in animals using nordefrin as compared to epinephrine. Nordefrin also demonstrated similar hemodynamic activity compared to norepinephrine. In addition, none of the animals receiving nordefrin developed hemodynamically significant ventricular dysrhythmias following defibrillation.
The present inventors have also earlier demonstrated improved changes in aortic diastolic pressure using a peripherally acting imidazoline with strong alpha-2 and weak alpha-1 agonist properties and a phenylethanolamine with strong alpha-2 and weak alpha-1 and beta-1 agonist properties.
Redding et al. demonstrated the importance of adrenergic agonists in CPR. In those studies, when adrenergic agonists were added to artificial respiration and closed-chest CPR, myocardial perfusion and resuscitation rates were improved compared to animals receiving CPR alone. Studies by Yakaitis and Otto confirmed these findings and established that it was the alpha agonist component of adrenergic drugs that were primarily responsible for the improvement in myocardial perfusion. By blocking the beta adrenergic agonist components of epinephrine, an alpha 1,2; beta 1,2 agonist, they were able to demonstrate comparable resuscitation rates compared to epinephrine alone, and diminished resuscitation rates when the alpha agonist components of epinephrine were blocked.
In several prior art studies, swine models have been used to simulate out-of-hospital cardiopulmonary arrest in humans. Because of similarities in thoracic and cardiovascular anatomy, swine are recognized as the model species of choice for anticipating the effects of drugs on human hearts during CPR.
One compound, 2-(2,6-diethyl-3-anilino)-2-imidazoline, also known as ST-91, represents the first member of the imidazoline class of adrenergic agonists to show beneficial effects in the swine model of cardiac arrest and CPR. ST-91 is known to be selective for peripheral action on adrenergic receptors. It is believed that the alkyl groups play an important role in preventing ST-91 from getting into the central nervous system and thus only the peripheral actions are observed in contrast to other imidazoline derivatives.
It would therefore be desired to provide improved adrenergic agonists that will enhance the outcome in patients suffering cardiac arrest. Also, drugs currently used to treat cardiac arrest often possess undesirable side effects, such as increased oxygen consumption and post-defibrillation ventricular dysrhythmias. It would be desirable to have a new drug or drugs for the treatment of cardiac arrest and other shock states which do not have these and other adverse side effects.